Novel therapeutic approach for cancer using four cardiovascular hormones.

BACKGROUND: The atrial natriuretic peptide (ANP) gene synthesizes four cardiovascular hormones, i.e. vessel dilator, long-acting natriuretic peptide, kaliuretic peptide and ANP, which decrease the number of human pancreatic adenocarcinoma cells in culture by 65%, 47%, 37%, and 34%, respectively. METHODS AND MATERIALS: None of the cardiovascular hormones has been investigated to determine whether they inhibit the growth of cancers in vivo. These four hormones were evaluated for their ability to inhibit the growth of human pancreatic adenocarcinomas in athymic mice. RESULTS: Vessel dilator (139 ng min(-1) kg(-1) of body weight) infused for 14 days completely stopped the growth of human pancreatic adenocarcinomas in athymic mice (n = 14) with a decrease in their tumour volume, while the tumour volume increased 69-fold (P < 0.001) in the placebo (n = 30)-treated mice. When these peptide hormones (each at 1.4 microg min(-1) kg(-1) body weight) were infused for 4 weeks, vessel dilator, long-acting natriuretic peptide and kaliuretic peptide decreased tumour volume after 1 week by 49%, 28%, and 11%, respectively, with a one- and 20-fold increase in the tumour volume in ANP- and placebo-treated mice. Cyclic GMP (2.4 microg min(-1) kg(-1) body weight) inhibited after 1 week the growth of this cancer 95%. CONCLUSIONS: These results suggest that these peptide hormones have useful anticancer properties, as they each inhibited the growth of the human pancreatic adenocarcinomas in vivo and three of the four peptide hormones decreased the volume of the tumours (up to 49%, i.e. vessel dilator). Part of their mechanism of action appears to be mediated by cyclic GMP.

Segmental degeneration in the cervical spine and associated changes in dorsal root ganglia.

Degenerative change in cervical segments C5-C7 was documented to determine whether osteo-ligamentous adaptations were age-related. In addition, companion morphological studies were carried out to determine whether parallel changes occurred in related soft tissues, including DRG. Independent of the provoking stimulus, aberrant soft tissue change may be expected with segmental degeneration. Two associations were identified: between the incidence of segmental degeneration and severity of DRG distortion, and between segmental degeneration and DRG inflammatory mast cell density. Peripheral type C cells seemed more susceptible to compression in circumstances of DRG distortion. In light of neuropeptide expression in these cell types, predominant type C cell compression may be clinically relevant in the noxious cascade contributing to the sensation of pain.

Selenium supplementation, baseline plasma selenium status and incidence of prostate cancer: an analysis of the complete treatment period of the Nutritional Prevention of Cancer Trial.

OBJECTIVE: To present the results (to January 1996, the end of blinded treatment) of the Nutritional Prevention of Cancer (NPC) Trial, a randomized trial of selenium (200 micro g daily) designed to test the hypothesis that selenium supplementation (SS) could reduce the risk of recurrent nonmelanoma skin cancer among 1312 residents of the Eastern USA. MATERIALS AND METHODS: Original secondary analyses of the NPC to 1993 showed striking inverse associations between SS and prostate cancer incidence. A subsequent report revealed that this effect was accentuated among men with the lowest baseline plasma selenium concentrations. The effects of treatment overall and within subgroups of baseline prostate-specific antigen (PSA) and plasma selenium concentrations were examined using incidence rate ratios and Cox proportional hazards models. RESULTS: SS continued to significantly reduce the overall incidence (relative risk and 95% confidence interval) of prostate cancer (0.51, 0.29-0.87). The protective effect of SS appeared to be confined to those with a baseline PSA level of

Muscle spindle distribution, morphology, and density in longus colli and multifidus muscles of the cervical spine.

STUDY DESIGN: Tissue blocks comprising muscle and bone from C5 to C7 segments were harvested at autopsy from 16 individuals ranging in age from 4 to 77 years. The prevertebral longus colli and postvertebral multifidus muscle pairs from one side in each individual were randomly selected for this study of muscle spindles. OBJECTIVES: To determine muscle spindle distribution, morphology, and density for the longus colli and multifidus in caudal segments of the human cervical spine, and to assess whether changes are evident from infancy to old age. SUMMARY OF BACKGROUND DATA: Age-related changes to the osteoligamentous framework of the cervical spine have been well documented. Postural modification accompanies these structural alterations, but there have been limited attempts to document whether muscle sustains a comparable level of morphologic alteration. Previous studies have examined muscle spindles in the neck muscles of various animal models and in a variety of isolated human muscles. However, most of these studies incurred bias through sampling and methodologic assumptions. METHODS: The longus colli and multifidus were resected between C5 and C7, and between left and right pairs selected randomly for spindle analysis. These vertebral segments were selected deliberately because they form the apex of the cervical lordosis and the site at which the greatest age-related modification occurs. The tissue was processed in paraffin, sectioned, and then stained by Masson's trichrome. Spindle characteristics were examined using light microscopy and analyzed by unbiased stereologic methods. A one-sample paired t test was used to ascertain whether the differences in spindle density between the two muscles were statistically significant. RESULTS: The longus colli has a high density of muscle spindles, which appear clustered and concentrated anterolaterally, away from the vertebral body. The multifidus has a low density of muscle spindles, which are found predominantly as single units concentrated closely to the vertebral lamina. No change in spindle distribution, morphology, and density were observed with age. CONCLUSIONS: The current study examined spindle characteristics for an intrinsic neck muscle pair whose coactivation contributes to segmental stability of the cervical spine. The distribution and morphology of muscle spindles differ between the longus colli and the multifidus. In addition, these muscles have significant differences in terms of mean spindle density. Spindle characteristics represent one of many factors that govern proprioceptive regulation in skeletal muscle, and in neck muscles, the central connectivity of these receptors remains undefined. Therefore, although there are anatomic differences between the neck flexor and extensor, the functional implications of these differences are not clear. It is also of interest that spindle characteristics remain unchanged in these intrinsic muscles whose underlying segments are subject to age-related osteoligamentous changes.

An analysis of cancer prevention by selenium.

The nutritional functions of selenium (Se) are recognized as being due to a number of Se-containing proteins. It is not clear, however, whether any of these function in the anti-tumorigenic effects of Se most of which have been demonstrated for Se exposures greater than those required for selenoprotein expression. Indeed, other anti-tumorigenic mechanisms have been demonstrated for certain Se-metabolites. The Nutritional Prevention of Cancer Trial found supplemental Se (200 microg/day, as Se-enriched yeast) to be associated with significant reductions in cancer risks in subjects with pre-treatment plasma Se concentrations below ca. 120 ng/ml (1.5 nmoles/ml), which level would appear to require food-Se intakes of ca. 1.5 microg/kg body weight/day. However, the putative anti-carcinogenic Se-metabolite(s) should be more relevant than total plasma Se as a supplementation target for cancer prevention. These may be components of the non-protein-bound fraction of Se in plasma, which constitutes 2-4% of total plasma Se.

Randomized, controlled chemoprevention trials in populations at very high risk for prostate cancer: Elevated prostate-specific antigen and high-grade prostatic intraepithelial neoplasia.

This is a report of research efforts underway at the Arizona Cancer Center. These efforts build upon Larry Clark's unanticipated clinical prevention trial results: those results indicated that 200 microg/day of selenium in selenized yeast decreased prostate cancer risk by almost 60%. The trials underway address various phases of the possible preventive activity of selenium. The first of these, for men who are suspected to have prostate cancer but who have had a biopsy revealing no evidence of cancer, will test the ability of selenium to prevent the development of clinical prostate cancer. The second is for men with high-grade prostatic intraepithelial neoplasia; the trial will test whether selenium will prevent the development of prostatic cancer in this high-risk group. The third trial is for men who have been diagnosed with prostate cancer and are scheduled for prostatectomy: the trial is designed to test whether evidence of selenium-linked changes can be identified in the tissue removed at prostatectomy. The fourth trial is for men who have been diagnosed with prostate cancer but who have chosen neither surgery nor irradiation; this trial will evaluate whether treatment with selenium will inhibit the progress of prostate cancer. Together, these trials will provide important information as to the prostate cancer chemopreventive potential of selenium.

SLE in a United States-Mexico border community.

This report describes the results of a clinic-based study conducted to verify a community-reported excess prevalence of systemic lupus erythematosus (SLE) and a possible connection between ethnicity and environmental factors in the reporting of SLE in the United States-Mexico border town of Nogales, Arizona. A community group in Nogales reported 37 cases of SLE in its community, suggesting a prevalence rate of 200 per 100,000. This report describes 19 definite and 7 probable cases of SLE using the 1982 American College of Rheumatology criteria. All definite and probable cases were self-identified, Mexican-American females. This yields a prevalence rate of 94 per 100,000, among the highest reported to date. The majority of cases resided within 3 miles of the United States-Mexico border and within 1 mile of the polluted Nogales Wash or ground wells with documented toxins. It remains to be determined whether this confirms that SLE is more common in Mexican-Americans or whether environmental factors, especially pollutants, are predominantly responsible. In addition to the need to be aware about the apparent increased risk of SLE in many Latin-Americans, clinicians should ask about possible environmental factors.

Comparative histochemical composition of muscle fibres in a pre- and a postvertebral muscle of the cervical spine.

References to histochemistry are extensive for human limb muscles but occur less frequently in relation to vertebral muscle. Most vertebral muscle literature has been concerned with muscle fibre characteristics in the lumbar and thoracic spine, due in large part to the incidence of low back pain and idiopathic scoliosis. However few studies have investigated the histochemical composition of neck muscles in humans: and, to our knowledge, no previous study has examined the antagonistic longus colli and multifidus muscle pair. In addition, while age-related segmental degeneration is most prominent between C5 and C7, it is not known whether these osteoligamentous changes are paralleled by changes in muscle fibre ratio. Tissue blocks comprising muscle and bone from C5-C7 segments were harvested at autopsy from 16 subjects with ages ranging from 4 to 77 years. The prevertebral longus colli and postvertebral multifidus muscle pairs were randomly selected from one or other side in each subject. The tissue was frozen, sectioned and histochemically stained for myofibrillar adenosine triphosphatase. Analysis of muscle fibre types was performed by light microscopy. Wilcoxon paired t-tests were used to ascertain whether intramuscular and intermuscular differences in fibre composition were significant. In addition, correlation and regression analyses were used to determine whether fibre type proportions changed in either muscle with increasing age. The present study has revealed histochemical differences between longus colli and multifidus at the level of the C5-C7 vertebral segments. Multifidus comprises a significantly greater proportion of type I than type II fibres. Longus colli comprises a significantly greater proportion of type II fibres than multifidus. Further there were no changes in fibre type proportion in either muscle with increasing age. These observations suggest that longus colli responds equally to postural and phasic demands, whereas multifidus is predominantly postural. Also it would appear that age-related structural alterations in lower cervical segments are not paralleled by changes in muscle fibre ratio.

Monitoring age-related changes of collagen content and vascularity in ganglia using unbiased stereological methods.

We describe for the first time application of unbiased stereological techniques to estimate total volume and volume fractions of interest in individual dorsal root ganglia (DRG). Volume estimates were obtained using a two-stage sampling design. Sections were systematically sampled following a random start, from DRG which were embedded in methacrylate and exhaustively sectioned. We further examined the efficiency of point counting irregular volume fractions housed in a regular reference volume. We found that the precision of volume estimates was relatively unaffected by exhaustive sampling, and that the magnitude of error was, in large part, determined by object shape.

Experiences at a large teaching hospital with levofloxacin for the treatment of community-acquired pneumonia.

Costs, patient outcomes, and susceptibility patterns of selected organisms after the implementation of guidelines for the treatment of community-acquired pneumonia (CAP) at a large community teaching hospital were analyzed to assess the benefit of the guidelines. The guidelines, implemented in September 1998, included recommendations for the use of levofloxacin as the preferred antimicrobial, with rapid intravenous (i.v.) to oral (p.o.) conversion. Purchase data for levofloxacin, ceftriaxone, and azithromycin were analyzed, as well as susceptibilities and demographic and outcome data for patients admitted in 1999 in diagnosis-related groups (DRGs) 89 and 90 (simple pneumonia with and without comorbidities, respectively). Patients in each DRG were divided into a levofloxacin use only (LUO) group and an all other therapies (AOT) group. Average length of stay (LOS), hospital costs, death rate, age, and ratio of oral to intravenous dosage administration were analyzed. A total of 571 patients in DRG 89 and 110 patients in DRG 90 were included. The average LOS for DRG 89 was not significantly different between LUO patients and AOT patients (3.56 +/- 2.23 days and 3.88 +/- 2.65 days, respectively). Average total costs were significantly higher for AOT patients ($3385 +/- $2937 versus $2892 +/- $2397 for LUO patients); similar trends but no significant differences were found in the DRG 90 group. In the LUO groups in both DRGs, patients were more than five times as likely to receive an oral dosage form than patients in the AOT group. For DRG 89, the death rate was significantly lower for the LUO group (1.29%) than the AOT group (7.1%). Susceptibility data for all organisms remained stable from 1998 to 1999. The average costs in the AOT groups suggest that total hospital costs for 1999 in the LUO group were $241,516 less than costs would have been before guideline implementation. Combined drug acquisition cost savings in 1999 for levofloxacin, ceftriaxone, and azithromycin were $21,115. The use of CAP treatment guidelines was associated with reductions in antimicrobial costs, total hospitalization costs, LOS, and death rate, without a detrimental effect on organism susceptibility.

The effects of dietary selenomethionine on polyamines and azoxymethane-induced aberrant crypts.

We evaluated the effects of dietary selenomethionine supplementation on colonic polyamine levels and the ability of L-selenomethionine supplementation to modulate the carcinogenic activity of azoxymethane (AOM) in the rat colon. Four-week-old male F344 rats were treated with 15 mg/kg body weight of AOM once a week for 2 weeks. Dietary selenomethionine at a concentration of either 1 or 2 ppm was administered in AIN-76A rodent diet to AOM-treated animals for 16 weeks. Aberrant crypt foci (ACF), precursor lesions of colon cancer, were investigated after the 16 week treatment course. Selenomethionine given in the diet at 2 ppm markedly reduced the number of aberrant crypt foci. The multiplicity of ACFs (i.e. the number of aberrant crypts/focus) and the percentage of microadenomas were also affected by selenomethionine in a dose dependent manner. However, evaluation of the colonic tissue polyamine levels between control and treated groups showed no significant difference. These results demonstrate that selenomethionine can modulate the development of AOM-induced premalignant lesions through a polyamine-independent mechanism.

A latent class mixed model for analysing biomarker trajectories with irregularly scheduled observations.

This paper considers a latent class model to uncover subpopulation structure for both biomarker trajectories and the probability of disease outcome in highly unbalanced longitudinal data. A specific pattern of trajectories can be viewed as a latent class in a finite mixture where membership in latent classes is modelled with a polychotomous logistic regression. The biomarker trajectories within a latent class are described by a linear mixed model with possibly time-dependent covariates and the probabilities of disease outcome are estimated via a class specific model. Thus the method characterizes biomarker trajectory patterns to unveil the relationship between trajectories and outcomes of disease. The coefficients for the model are estimated via a generalized EM (GEM) algorithm, a natural tool to use when latent classes and random coefficients are present. Standard errors of the coefficients are calculated using a parametric bootstrap. The model fitting procedure is illustrated with data from the Nutritional Prevention of Cancer trials; we use prostate specific antigen (PSA) as the biomarker for prostate cancer and the goal is to examine trajectories of PSA serial readings in individual subjects in connection with incidence of prostate cancer.

Amelioration with vessel dilator of acute tubular necrosis and renal failure established for 2 days.

Seventeen Sprague-Dawley rats had ischemic nonoliguric acute renal failure (ARF) induced by vascular clamping resulting in their preischemic blood urea nitrogen (BUN) and creatinine levels of 16 +/- 1 and 0.56 +/- 0.05 mg/dl to increase to 162 +/- 4 and 8.17 +/- 0.5 mg/dl, P < 0.001, respectively, at day 4 of postischemia. Vessel dilator, a 37-amino-acid cardiac peptide hormone (0.3 microg x kg(-1) x min(-1) ip), decreased the BUN and creatinine levels to 53 +/- 17 mg/dl and 0.98 +/- 0.12 mg/dl (P < 0.001) in another seven animals where ARF had been established for 2 days. Water excretion doubled with ARF and was further augmented by vessel dilator. Transthoracic echocardiography revealed left ventricular dilation as a probable cause of the increase in vessel dilator in the circulation with ARF, and vessel dilator infusion reversed this dilation. At day 6 of ARF, mortality decreased to 14% with vessel dilator from 88% without vessel dilator. Acute tubular necrosis was <5% in the vessel dilator-treated rats compared with 25% to >75% in the placebo-treated ARF animals. We conclude that vessel dilator improves acute tubular necrosis and renal function in established ARF.

Treatment with soybean-derived Bowman Birk inhibitor increases serum prostate-specific antigen concentration while suppressing growth of human prostate cancer xenografts in nude mice.

BACKGROUND: Bowman Birk inhibitor (BBI) is an anticarcinogenic serine protease inhibitor that may inhibit the protease activity of prostate-specific antigen (PSA) and the growth of human prostate cancer xenografts in nude mice. METHODS: Human prostate cancer xenografts were established by implanting LNCaP cells into the prostate glands of NCRNU-M athymic nude mice. The animals with established tumors were maintained on a control diet or diets supplemented with 1% BBI or 1%, 2%, or 3% BBI concentrate (BBIC) for 6 weeks. The serum PSA concentrations were determined before and after the BBI or BBIC treatment period. The final tumor loads were determined at autopsy. RESULTS: Treatment with BBI or BBIC decreased the final tumor load and increased the tumor doubling time and PSA density in the nude mice bearing human prostate cancer xenografts. CONCLUSIONS: BBI and/or BBIC could be useful for prostate cancer treatment.

Elevated atrial natriuretic peptides and early renal failure in type 2 diabetic Goto-Kakizaki rats.

The present investigation was designed to determine if atrial natriuretic peptides (ANPs) are increased in a spontaneous model of non-obese type 2 diabetes, the Goto-Kakizaki (GK) rat. Four peptide hormones originating from the ANP prohormone were increased twofold (P < .05) to sixfold (P < .01) in the circulation of GK rats compared with nondiabetic Wistar rats from which the GK colony was originally derived. Thus, ANP, long-acting natriuretic peptide (LANP), vessel dilator, and kaliuretic peptide were (mean +/- SE) 497 +/- 78, 1,285 +/- 105, 457 +/- 45, and 385 +/- 87 pg/mL in GK rats, versus 78 +/- 23, 542 +/- 77, 137 +/- 26, and 134 +/- 33 pg/mL, respectively, in Wistar rats. In evaluating the cause of the increased ANPs, the blood volume of GK rats (16.2 +/- 0.4 mL) was significantly (P < .01) increased compared with Wistar rats (9.5 +/- 0.3 mL). The ventricles of GK rats were not dilated when examined by transthoracic echocardiography, but the venous system was markedly distended. GK rats had a 48% to 79% decrease in renal function (ie, increased serum creatinine and blood urea nitrogen [BUN]) compared with Wistar rats. These results indicate that circulating ANPs are increased in the GK spontaneously diabetic rat secondary to (1) increased blood volume, which leads to increased synthesis and release of ANPs, and (2) renal failure, which results in a delayed metabolic processing of these peptides. The early combined increases of the four atrial peptides collectively may contribute to the hyperfiltration that occurs in early diabetes mellitus.

Selenium and prostate cancer prevention.

Prostate cancer is the second leading cause of cancer deaths in men, therefore it is increasingly important to understand its biology and epidemiology. New approaches for the primary and secondary prevention of prostate cancer are needed, including innovative uses of chemoprevention. This review provides an overview of the epidemiological data suggesting that higher intakes of selenium may reduce the risk of prostate cancer. In addition, a discussion of preclinical data is presented. Special emphasis is placed on the following areas: (1) chemical forms of selenium and antitumorigenic activity, (2) in vitro effects of selenite versus monomethylated selenium, and (3) current clinical intervention trials with selenium in prostate cancer. Chemoprevention, especially with dietary forms of selenium, is a promising new approach that presently is undergoing intensive investigation.

Decreased incidence of prostate cancer with selenium supplementation: results of a double-blind cancer prevention trial.

OBJECTIVE: To test if supplemental dietary selenium is associated with changes in the incidence of prostate cancer. PATIENTS AND METHOD: A total of 974 men with a history of either a basal cell or squamous cell carcinoma were randomized to either a daily supplement of 200 microg of selenium or a placebo. Patients were treated for a mean of 4.5 years and followed for a mean of 6.5 years. RESULTS: Selenium treatment was associated with a significant (63%) reduction in the secondary endpoint of prostate cancer incidence during 1983-93. There were 13 prostate cancer cases in the selenium-treated group and 35 cases in the placebo group (relative risk, RR=0.37, P=0.002). Restricting the analysis to the 843 patients with initially normal levels of prostate-specific antigen (< or = 4 ng/mL), only four cases were diagnosed in the selenium-treated group and 16 cases were diagnosed in the placebo group after a 2 year treatment lag, (RR=0.26 P=0.009). There were significant health benefits also for the other secondary endpoints of total cancer mortality, and the incidence of total, lung and colorectal cancer. There was no significant change in incidence for the primary endpoints of basal and squamous cell carcinoma of the skin. In light of these results, the 'blinded' phase of this trial was stopped early. CONCLUSIONS: Although selenium shows no protective effects against the primary endpoint of squamous and basal cell carcinomas of the skin, the selenium-treated group had substantial reductions in the incidence of prostate cancer, and total cancer incidence and mortality that demand further evaluation in well-controlled prevention trials.